Cyanobenzophenones



United States Patent 3,329,701 CYANOBENZOPHENONES Gabriel Saucy, Riehen,Switzerland, and Franklin Artell Smith, Nutley, and Leo HenrykSternbach, Upper Montclair, N.J., assignors to Hoifmann-La Roche Inc.,Nutley, N.J., a corporation of New Jersey No Drawing. Originalapplication June 14, 1962, Ser. No. 202,401, now Patent No. 3,117,965,dated Jan. 14, 1964. Divided and this application Nov. 4, 1963, Ser. No.321,284 Claims priority, application Switzerland, Mar. 9, 1962, 2,884/62 9 Claims. (Cl. 260-465) This application is a division of applicationSer. No. 202,401, filed June 14, 1962, now United States Patent No.3,117,965, issued Jan. 14, 1964. Application Ser. No. 202,401 was acontinuation-in-part of application Ser. No. 114,038, filed June 1,1961, now United States Patent No. 3,153,082, issued Oct. 13, 1964.

This application relates to novel intermediates for nitrogenheterocyclic compounds. Specifically, the nitrogen heterocycliccompounds are -phenyl-3H-1,4-benzodiazepines substituted in the benzoand/or phenyl ring by a radical selected from the group consisting ofcarbamyl, carbo-lower alkoxy, cyano and carboxy. More specifically, thenitrogen heterocyclic compounds are selected from the group consistingof compounds of the formula:

Ra CH2 and their acid addition salts;

wherein R is selected from the group consisting of hydrogen and loweralkyl; R and R are each selected from the group consisting of carbamyl,carbo-lower alkoxy, cyano, carboxy, hydrogen and halogen; and at leastone of R and R is selected from the group consisting of carbamyl,carbo-lowed alkoxy, cyano and carboxy.

As used in this application the term lower alkyl refers to both straightand branched chain hydrocarbon radicals such as methyl, ethyl, propyl,isopropyl and the like. The term carb'o-lower alkoxy refers toesterified carboxy radicals, for example carbomethoxy, carboethoxy andthe like. The term halogen includes all four halogens, i.e. bromine,chlorine, fluorine and iodine. When R or R is halogen, bromine, chlorineand fluorine are especially preferred.

The nitrogen heterocyclic compounds of the invention conforming toFormula I above are basic in character and for-m acid addition saltswith medicinally acceptable acids. The compounds of Formula I formmedicinally acceptable acid addition salts with both organic andinorganic acids as for example nitric acid, sulfuric acid, hydrochloricacid, hydrobromic acid, p-toluene sulfonic "ice acid, fumaric acid,succinic acid, maleic acid, formic acid, acetic acid, nitric acid, andthe like.

The novel nitrogen heterocyclic compounds of this invention conformingto Formula I above have valuable medicinal properties and are useful assedatives, trauquilizers, muscle relaxants and anticonvulsants.Especially preferred are the compounds of Formula I above wherein R iscyano and is in the7-position. They can be administered either in thebase form or as an acid addition salt, with dosage adjusted toindividual requirements, in conventional pharmaceutical forms such astablets, capsules, suppositories, injectable solutions-and the like.They can be taken internally, as for example orally or parenterally.

The novel heterocyclic nitrogen compounds of the invention conforming toFormula I above can be prepared by several different routes. Forexample, compounds wherein R is in the 7-position can be prepared from a5 methyl 2 aminobenzophenone by -a variety of methods. According to onemethod of the invention a 5 methyl 2 aminobenzophenone can be acylatedto yield a 2 acetamino 5 methylbenzophenone which can then in turn beoxidized to yield a 2-acetamino-5-carboxybenzophenone. This lattercompound can then be hydrolyzed to a 2-amino-5-carboxybenzophenone whichin turn can be esterified to yield a Z-amino-S-carbo-loweralkoxybenzophenone, which latter compound can be reacted with ahaloacetyl halide, such as for example bromoacetyl bromide, to yield a2-haloacetylamino-S-carbo-lower alkoxybenzophenone which in turn can becyclized to yield a compound corresponding to Formula I above wherein Ris carbo-lower alkoxy. This latter compound can be reacted with ammoniato yield a compound according to Formula I above wherein R is carbamyl.This latter carbamyl compound can be converted by dehydration to thecorresponding cyano compound. Especially preferred as ha-loacetylatingagents are chloroacetyl chloride and bromoacetyl bromide.

An alternative route comprises reacting a 2-amino- [benzophenone withglycine or an ester thereof in order to directly effect cyclization to acompound conforming to Formula I above. The conversion carboxy tocarbamyl to cyano can occur either all or in part on theaminobenzophenone intermediate or after the heterocyclic nucleus isformed.

Another alternative preparation route can be conducted by converting the2-acetamino-5-carboxybenzophenone into the corresponding carbamylcompound and, in turn, dehydrating this to the corresponding cyanocompound (i.e. a Z-acetamino-S-cyanobenzophenone) which can, in turn,then be hydrolyzed to a -2-amino-5cyanobenzophenone which lattercompound can be reacted with a ha-loacetyl halide to yield a 2-haloacetamino-5-cyano benzophenone which can then be cyclized to acompound conforming to Formula I above wherein R is cyano. In thissequence, it is also preferred to use a bromoacetyl or chloroacetylhalide as the haloacetylating agent.

As can be appreciated from the above genera] description, the conversionof carboxy to carbamyl to cyano can be conducted on any of the variousintermediate benzophenones before the formation of the heterocyclicnucleus conforming to Formula I above. It can also be conducted after acompound conforming to Formula I above containing a carboxy substituentis formed. Fur thermore, the conversion of carboxy to carbamyl can'beconducted before the heterocyclic nucleus is formed with wherein R isselected from the group consisting of hydrogen, acetyl and haloacetyl; Ris selected from the group consisting of hydrogen and lower alkyl; R isselected from the group consisting of hydrogen and halogen; and R isselected from the group consisting of carbamyl, carbo-lower alkoxy,cyano and carboxy.

More specifically, this application comprehends novel intermediates ofthe formula (III) wherein R R and R have the same meaning as above and Ris selected from the group consisting of hydrogen and halogen. When R ishalogen, it is preferably selected from the group consisting ofchlorine, bromine and iodine, with the former two being especiallypreferred.

Also, this application comprehends novel intermediates of Formula IIIwherein R is halogen, R is cyano and R is hydrogen.

Still another route of preparing the compounds conforming to Formula Iabove comprises converting a compound conforming to Formula II abovewherein R is haloacetyl into a correspondingZ-aminoacetaminobenzophenone, and then cyclizing the latter compoundinto a heterocyclic compound conforming to Formula I above. TheZ-aminoacetaminbenzophenone compounds are not a part of this invention,but their preparation is disclosed herein in order that the presentdisclosure may be complete.

The following examples are illustrative but not limitative of theinvention. All temperatures are in degrees centigrade.

Example 1 Over a period of 30 minutes, 71 g. of potassium permanganatewas added in small portions to a stirred refluxing mixture of 50 g. of2-acetamino-5-methylbenzophenone and 2.5 liters of water. The resultingmixture, containing starting material, the oxidation product andmanganese dioxide was allowed to reflux for an additional two hours andwas then filtered hot through a filter aid. The clear filtrate wasacidified with approximately 100 ml. of 3 N hydrochloric acid and cooledin a refrigerator overnight. The precipitated product,Z-acetamino-S-carboxybenzophenone was filtered, washed with water anddried for 12 hours in vacuo at 50. Upon crystallization from ethanol theproduct formed slightly yellow needles melting at 211.

The 2 acetamino 5 methylbenzophenone used as a starting material in thisexample is not a part of this invention but its preparation is disclosedhereunder in order that the present disclosure may be complete.

A mixture consisting of 170 g. of 2-amino-5-methylbenzophenone, 300 ml.of acetic anhydride and 600 ml. of benzene was stirred and refluxed for2 hours. The reaction mixture was cooled in an ice bath and theprecipitate formed collected on a suction funnel and washed with ether,yielding 2-acetamino-5-methylbenzophenone, M.P. 154155.

Example 2 A mixture of 40 g. of Z-acetamino-S-carboxylbenzophenone, 400ml. absolute methanol and 8 g. p-toluene sulfonic acid was refluxed for24 hours. While still hot, about A of the solvent was evaporated, saidevaporation resulting in the precipitation of the reaction product,2-amino-5-carbornethoxybenzophenone. After cooling overnight at 0, theprecipitated product was filtered off, washed with col-d ether and driedin vacuo at 60. After crystallization from ethanol, the product formedprisms melting at 173-l74.

Example 3 During 30 minutes a solution of 7.8 ml. of brornoacetylbromide in 210 ml. of dioxane was added in portions to a solution of20.4 g. of 2-amino-5-carbo-methoxybenzophenone in 200 ml. of dioxane,said solution being maintained at 20. Afterwards, 20 ml. of 3 N sodiumhydroxide was added within about 1 hour. The reaction mixture, afterbeing permitted to stand overnight, Was extracted with ether and theether layer washed four times with Water. After drying over sodiumsulfate, the ether solution was concentrated to about 50 ml. Then ml. ofbenzene was added and the resulting solution concentrated to about 100ml. Said concentrated solution was then permitted to stand overnight at0 and then filtered. The precipitate product was crystallized fromacetone to yield light yellow needles of 2-bromoacetamino-S-carbomethoxybenzophenone melting at 151l52.

Example 4 5 g. of 2-bromoacetamino-S-carbomethoxybenzophenone wasreacted for 20 hours at room temperature with 100 ml. of a 40% solutionof ammonia in methanol. The resulting crude reaction product waspurified by chromatography on activated alumina (25-fold amount)containing 6% of water. After eluting with benzene and then with etherto remove unidentified contaminants, the product, 5 phenyl-7-carbomethoxy l,4-benzodiazepin-2- (1H)-one, was obtained by eluting withacetone. Upon crystallization from methanol the product formed prismsmelting at 2l9-220.

Example 5 4.275 g. of 5-phenyl-7-carbomethoxy-l,4-benzodiazepin-2(1H)-one was dissolved with warming in a mixture of 43 ml. of dioxaneand 43 ml. of ethylene glycol. After cooling to 20, 86 ml. ofconcentrated aqueous ammonia (58% ammonium hydroxide in water) was addedand the resulting solution permitted to stand at room temperature for 8days. The solution was then filtered and the so-obtained precipitatewashed with methanol and ether and dried in vacuo to yield7-carbamyl-5-phenyl- 3H-1,4-benzodiazepin-2(1H)-one melting at 268-271(dec.).

Example 6 42.5 g. of 2-acetamino-5-carboxybenzophenone was dissolved in700 ml. of chloroform containing 15 g. of triethylamine. To thissolution 16 g. of ethyl chlorocarbonate was added dropwise in the cold.The reaction mixture was stirred 3 hours, after which gaseous ammoniawas introduced in the cold. The reaction mixture was then kept at roomtemperature for two days and then filtered. The filtrate was acidifiedand the chloroform layer evaporated to dryness. The residue obtained waswashed with water and the water insoluble product so-ob- Example 7 34 g.of Z-acetamino-S-carbamylbenzophenone was dissolved in 250 ml. ofethylene dichloride and treated with 33 ml. of phosphorus oxychloride,the latter reagent being introduced dropwise at 65. Heating at 65 wascontinued for 2 hours after which the reaction mixture was cooled andpoured into 600 ml. of a mixture of ice and water. The organic layer wasseparated and washed with water until neutral, then dried over magnesiumsulfate and concentrated in vacuo, yielding crude Z-a-cetamino-S-cyanobenzophenone which was filtered and washed with a mixture of onepart benzene and four parts petroleum ether to yield a first crop ofproduct. The filtrate was concentrated to dryness to yield a second cropof the reaction product.

Example 8 8.7 g. of Z-acetamino-S-cyanobenzophenone obtained as thesecond crop according to the procedure of Example 7 above was taken upin 100 ml. of methanol and treated, while the solution was still warm,with 50 ml. of 30% aqueous sodium hydroxide solution, whereupon acrystalline product separated almost immediately. After the reactionmixture had cooled down to room temperature (i.e. after about 2 to 3hours standing) the product was filtered off, washed with water, driedand crystallized twice from alcohol to yield 2-amino-5-cyanobenzophenonemelting at 165.5166.1.

Example 9 Example 10 10.5 g. of Z-bromoacetamino-5-cyanobenzophenonedissolved in 35 cc. of dimethylformamide was poured into 525 cc. ofliquid ammonia. The ammonia was allowed to evaporate and the residuetreated with water and methylene chloride. The product was transferredfrom the methylene chloride solution to 10% hydrochloric acid which inturn was alkalized with sodium carbonate and the product extracted intotoluene and methylene chloride. After drying the resulting solution, themethylene chloride was distilled off and the toluene solution wasretfluxed overnight using a Dean-Stark separator to remove the waterformed in the ring closure. The product,7-cyano-5-phenyl-3H-1,4-benzodiazepin-2l(lH)-one, was obtained afteradding petroleum ether to the toluene solution, and aftercrystallization from nitromethane melted at 253-255 Example 11 6.66 g.of 2-amino-5-cyanobenzophenone was treated in 70 cc. of pyridine and 1.5g. of piperidine with 11.2 g. of glycine ethyl ester hydrochloride. Thereaction'mixture was refluxed for 16 hours after which the solvent wasremoved by distillation and the residue partitioned between ether andwater. The ether extract after drying was concentrated for crops 1 and2. Crop 2 was largely recovered starting material whereas crop 1 uponrecrystallization from methylene chloride afforded the product 7-cyano-S-phenyl-SH-1,4-benzodiazepin-2/(2H) one hydrochloride. Afterseveral recrystallizations from alcohol it melted at 238 (dec.).

Example 12 3.5 g. of 7-cyano-5-phenyl-3H-1,4-benzodiazepin- 2(lH)-onewas dissolved in 47 cc. of methanolic sodium met-hoxide prepared from0.33 g. of sodium. 4.7 cc. of methyliodide was added and the reactionmixture then stirred 3 hours at room temperature. The solvent wasremoved in vacuo and the residue treated with water. Recrystallizationfrom benzene-ether followed by extraction with ether alone afforded7-cyano-1-methyl-5-phenyl-3H 1,4-benzodiazepin-2 (1H)-one melting at158-160".

Example 13 A suspension of 50 g. of5-methyl-2-acetamino-2-fluorobenzophenone in a solution of 50 g. ofmagnesium sulfate in 2.5 liters of water was heated to reflux. To thisg. of potassium permanganate was added with vigorous stirring over aperiod of 5 hours. Some foaming occurred and all the reagent was usedup. After allowing the brown suspension to cool to about 70 it wasfiltered through a suction funnel. The last traces of magnesium dioxidewere then removed by filtration without vacuum. Upon acidification ofthe clear filtrate with concentrated hydrochloric acid (Congo red) avoluminous precipitation of S-carboxy-2-acetamino-2-fluorobenzophenoneoccurred. This was collected on a funnel, thoroughly washed with waterand dried in a vacuum oven at 70. Crystallization from methanol yieldedcolorless needles melting at 251-252".

The 5-methyl-2-acetamino-2-fiuorobenzophenone used as a startingmaterial above is not a part of this invention but its preparation isherein set forth in order that this disclosure may be complete.

160 g. of o-fiuorobenzoyl chloride was heated with stirring to To thisadded, over a period of about 30 minutes, 47.2 g. of ptoluidine. Theresulting mixture was slowly heated to 138 and then 100 g. of zincchloride added thereto over a period of about 30 minutes. To completethe reaction the temperature was gradually raised within 1 hour to225-2'30 and kept for 2 hours at this temperature. After the reactionmixture had cooled to 100, 800 ml. of hot water was slowly added and thehot aqueous phase siphoned oil". This extraction with hot water wasrepeated 3 times. The residual brown water insoluble solid washydrolyzed by refluxing for 6 hours with a mixture of 70 ml. of water,100 ml. of acetic acid and ml. of concentrated sulfuric acid. Theresulting reaction mixture was extracted with ether and petroleum ether.The organic layers were washed 4 times with Water, 3 times with 3 Nsodium hydroxide and again 3 times with water. After drying over sodiumsulfate, the organic extracts were concentrated in vacuo to yield crudeS-methyl- Z-amino-2'-fluorobenzophenone, which upon crystallization frombenzene-hexane, melted at 68.5-69.5 (yellow needles).

68.3 g. of the crude 5-methyl-2-amino-2-fluorobenzophenone preparedabove and a mixture consisting of 130 ml. of anhydrous benzene, 130 ml.of acetic anhydride and 130 ml. of pyridine were heated on a steam bathfor 2 hours, after which 200 ml. of methanol was added in order todestroy the excess of acetic anhydride. This caused the reaction mixtureto boil for several minutes. After evaporation of A4 of the solvents,the resulting solution was kept overnight at 0". The precipitate whichseparated was filtered oif and washed with petroleum ether. After dryingin vacuo, S-methyl-2-acetamino-2-fluorobenzophenone was obtained and,upon crystallization from benzene, formed almost colorless prismsmelting at 162- 163.

Example 14 30.1 g. of S-carboxy-2-acetamido-2'-fluorobenzophenone weredissolved in 400 ml. of chloroform containing 11 g. of triethylamine. Tothis a solution of 12 g. of ethyl colorca-rbonate in 50 ml. of colorformwas added with stirring over a period of 1 hours at 0-5 The reactionmixture was then stirried for 3 hours at room temperature after whichgaseous ammonia was introduced at -5 The resultant mixture was stirredovernight at room temperature. A precipitate of-carbamyl-2-acetamino-2'- fiuorobenzophenone formed, was collected on afunnel, washed with water and dried in vacuo at 60. The filtrate wasextracted with chloroform and washed in 3 portions with a total of 300ml. of 1 N sodium hydroxide and then with water. The chloroformextracted was then dried over sodium sulfate and evaporated to dryness,to yield an additional quantity of5-carbamyl-2-acetamino-2-fluorobenzophenone, which, aftercrystallization from ethanol formed colorless, hexagonal plates meltingat 221222.

Example 15 A suspension consisting of 38.09 g. of S-carbamyl-Z-acetamino-2'-fluorobenzophenone, 380 ml. of ethylene dichloride and 38ml. of phosphorus oxychloride was heated to reflux for 5 hours. Theresulting solution was cooled and poured into 700 ml. of ice and water.The organic layer was separated and washed with water, 1 N sodiumhydroxide and water, and then dried over sodium sulfate and concentratedin vacuo to dryness. The crude product was crystallized from methanol togive fine pale yellow needles of5-cyano-2-acetamino-2'-fluorobenzophenone melting at 144-145.

Example 16 A suspension of 3.33 g. of the crude5-cyano-2-acetamino-2'-fluorobenzophenone prepared in Example 13 abovein 333 ml. of methanol and 120 ml. of 3 N sodium hydroxide was stirredat room temperature for 2 /2 days. The product was filtered off, washedwith water and crystallized from about 250* ml. of benzene to yield5-cyano-2-amino-2'-fluorobenzophenone as fine yellow needles which aftercrystallization from benzene melted at 128129.

Example 17 12 g. of 5-cyano-2-amino-2'-fluorobenzophenone dissolved in200 m1. of anhydrous ether containing 3.96 g. of pyridine was treated at0 with 11.2 g. of bromoacetyl bromide in 50 ml. of anhydrous ether. Theresulting suspension was stirred for /2 hour at 0 and for 3 hours atroom temperature. The resultant5-cyano-2-bromoacetamino-2'-fluorobenzophenone was not isolated, butabout 100 ml. of liquid ammonia was introduced into the reaction flaskusing a Dry Ice-acetone condenser. After stirring for 3 hours at reflux,the Dry Ice condenser was replaced with a conventional condenser and theammonia allowed to evaporate overnight. 100 ml. of water was then addedand the reaction mixture stirred for 1 hour at room temperature.Insoluble material was then filtered off and washed with water andether. After drying in vacuo, a brown solid material was obtained whichupon crystallization from a mixture of methylene chloride and benzeneyielded a pink micro crystalline material. The latter material washeated in an open tube to 170 for 30 minutes. After cooling, a brownsolid was obtained, which was crystallized 3 times from methanol usingactivated charcoal in order to decolorize the substance. This procedureyielded colorless needles of7-cyano-5-(2-fluorophenyl)-3H-1,4-benzodiazepin 2 (1H)-one melting at239240.

Example 18 A suspension of 10 g. of5-methyl-2-acetamino-2'-chlorobenzophenone in 500 ml. of water washeated to reflux. In small portions and with vigorous stirring 10 g. ofpotassium permanganate was added to the refluxing mixture. The mixturewas kept at reflux temperature for 8 hours. The hot reaction mixture wasthen filtered through a diatomaceous earth filter aid and the filtrateacidified with 2 N hydrochloric acid. The resulting white precipitatewas filtered off, washed with water and dried in vacuo yielding 2acetamino-5-carboxy-2-chlorobenzophenone as a white powder which, afterbeing crystallized 3 times from methylene chloride-ethanol, melted at263- 265.

The 5-methyl-2-acetamino-2'-chlorobenzophenone used as a startingmaterial above is not a part of this invention but its preparation isset forth herein in order that the present disclosure may be complete.

39 g. of o-chlorobenzoyl chloride was warmed to and then, with stirring,10.7 g. of p-toluidine was added and the mixture heated to 182. 20 g. ofanhydrous zinc chloride was then added and the temperature raised to220. The reaction mixture was kept at 220 for another hour. Aftercooling to 200 ml. of water was added and the mixture heated to refluxfor 5 minutes with vigorous stirring. The hot water layer was decantedand the procedure repeated 3 times.

The water insoluble residue was then refluxed for 10 hours with amixture of 25 ml. of water, 35 ml. of acetic acid and 50 ml. ofconcentrated sulfuric acid. The resulting dark solution was cooled,poured into ice water and the mixture extracted with ether. The ethersolution was shaken with 2 N sodium hydroxide. Concentration of the darkether solution yielded 5-methyl-2-amino-2'-chlorobenzophenone as ayellow oil which after being crystallized 3 times from hexane melted atl06107.

A mixture of 10 g. of 5-methyl-2-amino-2'-chlorobenzophenone, 10 ml. ofacetic anhydride, 5 m1. of pyridine and 100 ml. of benzene was heated toreflux for 2 hours. The solvent was removed in vacuo and the residue wasrecrystallized twice from acetone-hexane yielding crystals of5-methyl-2-acetamino-2'-chlorobenzophenone melting at 158.

Example 19 A solution of 3.2 g. of2-acetamino-5-carboxy-2'-chlorobenzophenone, 50 ml. of chloroform and 1ml. of triethylamine was treated in the cold with 1.1 g. of ethyl'chlorocarbonate. The reaction mixture was stirred for 2 hours afterwhich a vigorous stream of gaseous ammonia was introduced for hour. Thereaction mixture was kept at room temperature overnight and then morechloroform added to dissolve the precipitate. The chloroform solutionwas washed with 2 N hydrochloric acid, water, 2 N sodium hydroxide andagain with water. It was then dried with sodium sulfate and concentratedto dryness. This yielded white crystals of 2-acetarnino5-carbamyl2'-chlorobenzophenone which upon crystallization from ethanol formsprisms melting at 216-217.

Example 20 4.3 g. of 2-acetamino-S-cyano-2'-chlorobenzophenone wasdissolved in 70 ml. of hot (50) methanol. To this hot solution 25 ml. of30% aqueous sodium hydroxide was added. The mixture was kept at roomtemperature for 3 hours then diluted with water and extracted withmethylene chloride. The methylene chloride solution was dried withsodium sulfate and evaporated. The residue was crystallized from benzeneyielding yellowish prisms of 2 amino-5-cyano-2'-chlorobenzophenonemelting at 151l52.

Example 22 13 g. of bromoacetyl bromide was introduced at 25 into asuspension of 13 g. of 2-amino-5-cyano-2-chlorobenzophenone and 250 ml.of absolute ether. After the addition had been completed, the mixturewas stirred at room temperature for hours. The resulting yellowishprecipitate was then filtered off, washed with water and dried in vacuo.The residue upon being twice recrystallized, yielded2-bromoacetamino-5-cyano-2'-chlorobenzophenone melting at 158-159.

Example 23 A solution of 4 g. of2-amino-4-cyano-2'-(2-chlorobenzoyl)-acetanilide in 40 ml. of pyridinewas heated to reflux for 16 hours. The pyridine was removed in vacuo andthe residue recrystalized from ethanol. There was otbained a firstfraction of 1.5 g. of crystals melting at 277-279". It was discarded.The second fraction upon being twice recrystallized from ethanol yielded7-cyano- 5 (2 chlorophenyl) 3H-l,4-benzodiazepin-2(lH)-one melting at232-233".

The 2 amino-4'-cyano-2'(Z chlorobenZoyl) -acetanilide used above as astarting material is not a part of this invention but its preparation isdisclosed herein in order that the present disclosure may be complete.

14 g. of 2-bromoacetamino-5-cyano-2-chlorobenzophenone was added to 200ml. of liquid ammonia. A yellow solution formed. The ammonia waspermitted to evaporate overnight and the crystalline residue was treatedwith water and choloroform. The chloroform layer was extracted with 2 Nhydrochloric acid and the acid extract was diluted with sodium hydroxidewhereupon 2- amino-4'-cyano-2'-(2-chlorobenzoyl)-acetanilide separatedas a white precipitate, which was filtered off, washed with water anddried in vacuo. After 2 crystallizations from ethanol-hexane thecompound melted at 170172.

Example 24 A solution of 1.0 g. of 2-amino-2'-cyanobenzophenone in 85ml. of anhydrous ether, cooled and stirred in an ice bath, was treatedwith a solution of bromoacetyl bromide 1.1 g.; 5.4 m. moles) in ml. ofether. The reaction mixture was stirred for 45 minutes and then 30 ml.of water was added. Stirring was continued for minutes and the mixturefiltered. The precipitate was dissolved in 25 ml. of methylene chloride,washed with 30 percent (w./w.) sodium carbonate ml.), water (2X20 ml.)dried and concentrated. The residue was recrystallized from an acetonehexane mixture to give 2-bromo-2-(Z-cyanobenzoyl)-acetanilide as whiteneedles, melting at 1446.

The above-mentioned 2-amino-2'-cyanobenzophenone, its process ofpreparation and intermediates therefor, are not a part of this inventionbut such are disclosed hereinbelow in order that the present disclosuremay be complete.

A mixture of 176 g. of o-fluoro benzoyl chloride and 64 g. ofp-chloroaniline was stirred and heated to 180, at which temperature 87g. of zinc chloride was introduced, the temperature raised to 200-205and maintained there for forty minutes. The golden colored melt wasquenched by the careful addition of 500 ml. of 3 N hydrochloric acid andthe resulting mixture refluxed for five minutes. The acid solution wasdecanted and the process repeated three times to remove allo-fluorobenzoic acid. The grey granular residue was dissolved in 300 ml.of 75% (vol/vol.) sulphuric acid and refluxed for forty minutes tocomplete hydrolysis. The hot solution was poured over 1 kg. of ice anddiluted to two liters with water. The organic material was extractedwith four 300 ml. portions of methylene chloride which were subsequentlywashed with two 500 ml. portions of 3 N hydrochloric acid to removetraces of p-chloroaniline, three 500 ml. portions of 5 N sodiumhydroxide solution to remove o-fluorobenzoic acid, and finally two 200ml.

10 portions of saturated brine solution. The methylene chloride extractwas dried over anhydrous sodium sulphate and the solvent removed to givethe crude aminobenzophenone. Recrystallization from methanol gaveZ-amino-S- chloro-2'-fluorobenzophenone yellow needles, (MP. 94- 95 50.0g. of 2-amino-5-chloro-2-fluorobenzophenone in 300 cc. oftetrahydrofuran was hydrogenated at atmospheric pressure in the presenceof 10 g. of charcoal (Norite), 30.0 g. of potassium acetate and 2.5 cc.of a 20% palladous chloride solution (20% by weight of palladium). Afteran initiation period varying from ten minutes to an hour, hydrogenuptake was rapid and stopped completely after the absorption of thetheoretical amount. Filtration of the catalyst over a Hyflo pad andremoval of the solvent left a yellow crystalline residue. The crudemixture of ketone and potassium acetate was partitioned betweenmethylene chloride (300 cc.) and water (1 L). The layers were separatedand the water layer washed with methylene chloride (3 X 50 cc.). Theorganic layers were combined, washed with 3 N sodium hydroxide solution(2 50 cc.), water (3 X cc.), saturated brine solution (3X 100 cc.),dried over anhydrous sodium sulfate and filtered. The solvent wasremoved and the product recrystallized from ethanol to give2-amino-2'-fluorobenzophenone as yellow prisms melting at 126-8 Asolution of 10.0 g. of 2-amino-2-fluorobenzophenone in 20 ml. ofconcentrated sulfuric acid was added slowly to a cooled solution of 4.0g. of sodium nitrite in 40 ml. of concentrated sulfuric acid, keepingthe temperature below 10. The reaction mixture was stirred at roomtemperature for one hour, cooled in an ice bath and carefullyneutralized with a 30% (w./w.) solution of sodium carbonate. Theresulting solution of diazonium salt was then added over a period ofthirty minutes to a vigorously stirred, ice cold mixture of 100 ml. ofbenzene and a solution of 6 g. of sodium cyanide, 4.5 g. of coppercyanide and 2.5 g. of sodium bicarbonate in 40 ml. of water. The mixturewas stirred at room temperature for one hour, then for five minutes at50, cooled and the layers separated. The aqueous layer was extractedwith 100 ml. of benzene. The organic layers were combined, washed with100 ml. of water, 50 ml. of saturated brine and evaporated to a brownoil. The oil was dissolvedin ether and filtered through 25 g. of Grade Ineutral alumina. The solution was concentrated and crystallized from anether, petroleum ether (B.P. 30-60) mixture to give2-cyano-2'-fluorobenzophenone, as pale yellow rods, melting at 734.

A mixture of 7.6 g. of 2-cyano-2-fluorobenzophenone, and 6.7 g. ofbenzylamine in 70 ml. of dry toluene was refluxed for two hours and thenconcentrated, under reduced pressure, to a bright green oil. The oil wasdissolved in 100 ml. of methylene chloride, washed with water (3 X 75ml.), dried over anhydrous sodium sulfate, filtered and concentrated.Crystallization from ether gave 2-benzylamino-2'-cyanobenzophenone, asyellow rods, melting at 142-1435".

A mixture of 6.0 g. of 2-benzylamino-2'-cyanobenzophenone and 1.0 g. of10% palladium on charcoal and 1.4 ml. of concentrated hydrochloric acidin ml. of glacial acetic acid was reduced with hydrogen. The reactionwas stopped after forty minutes, when 1.15 mmoles of hydrogen had beenadsorbed, filtered, neutralized with ammonium hydroxide at 10-15 andextracted with methylene chloride (3 X 100 ml.). The organic layers werecombined, washed with 100 ml. of 30% (w./w.) sodium carbonate solution,3X 75 ml. of water, dried over anhydrous sodium sulfate, and evaporated.The residue was crystallized from an acetone, hexane mixture to giveZ-amino-2'-cyanobenzophenone, as yellow plates melting at l32-3.

A solution of 0.5 g. of the above-prepared 2-bromo-2'- (2-cyanobenzoyl)acetanilide in 5 ml. of dichloromethane, was added to 15 ml. of liquidammonia. The reaction mixture was stirred for five minutes and then theammonia and solvent were removed under reduced pressure (no externalheating). The residual oil was dissolved in 25 ml. of dichloromethane,and the resulting mixture filtered. Hexane was then added to thedichloromethane extract and the product was filtered off yielding5-(2-carboxyphenyl)-3H-1,4-benzodiazepin-2(1H)-one as an amorphous whitepowder, softening at 185, crystallizing at 190 and melting at 215-30".

We claim:

1. A compound of the formula wherein R is selected from the groupconsisting of hydrogen and lower alkyl; R is selected from the groupconsisting of hydrogen and halogen; R is cyano and R is selected fromthe group consisting of hydrogen and halogen.

2. Z-acetamino-S-cyanobenzophenone.

3. 2-acetamino-5-cyano-2-halobenzophenone.

4. 2-haloacetamino-5-cyanobenzophenone.

5. 2-haloaceta'mino-5-cyano-2-halobenzophenone.

6. 2-bromoacetamino-5-cyanobenzophenone.

7. A compound as in claim 1 wherein R is cyano and is in the 5-positionof the benzophenone moiety.

8. Z-acetamino-5-eyano-2-fluorobenzophenone.

9. 2-halo-acetamino-5-cyano-2-fiuorobenzophenone.

No references cited.

CHARLES B. PARKER, Primary Examiner.

DOLPH H. TORRENCE, Assistant Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No 3 ,329,70l July 4, 1967 Gabriel Saucy et It is certified that error appears inthe above identified patent and that said Letters Patent are herebycorrected as shown below: Column 1, line 48, "carbo-lowed" should readcarbo-lower Column 4, line 11, "5-carboxylbenzo" should read Column 6,line 34, "To this added" should 5-carboxybenzoread To this was addedline 74, "colorcarbonate" should read chlorocarbonate same line 74,"coloroform" should read chloroform Column 7, line 1, "stirried" shouldread stirred line 29, "3.33 g." should read 33.3 g.

Signed and sealed this 13th day of January 1970.

(SEAL) Attest:

WILLIAM E. SCHUYLER, JR.

Edward M. Fletcher, Jr.

Commissioner of Patents Attesting Officer

1. A COMPOUND OF THE FORMULA